Indium(III) triflate catalysed transacetalisation reactions of diols and triols under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2012.07.048

Acyclic acetals and ketals undergo transacetalisation in the presence of catalytic quantities of indium(III) triflate (In(OTf)₃) and diols or triols under solvent-free conditions to generate the corresponding cyclic acetals and ketals in excellent yield. The methodology has been further developed to encompass a tandem acetalisation-acetal exchange protocol, which provides a facile and high yielding route to cyclic ketals from unreactive ketones under very mild reaction conditions.

Full text of DOI:10.1016/j.tet.2012.07.048

Tetrahedron 68 (2012) 7775e7781
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Indium(III) triflate catalysed transacetalisation reactions of diols and triols under
solvent-free conditions
*
Brendan M. Smith, Tomasz M. Kubczyk, Andrew E. Graham
Department of Science and Sport, University of Glamorgan, Pontypridd CF37 4AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Acyclic acetals and ketals undergo transacetalisation in the presence of catalytic quantities of indium(III)
triflate (In(OTf)3) and diols or triols under solvent-free conditions to generate the corresponding cyclic
acetals and ketals in excellent yield. The methodology has been further developed to encompass a tan-
dem acetalisation-acetal exchange protocol, which provides a facile and high yielding route to cyclic
ketals from unreactive ketones under very mild reaction conditions.
Received 31 January 2012
Received in revised form 22 June 2012
Accepted 13 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indium(III) triflate
Transacetalisation
Glycerol valorisation
Solvent-free reactions
Tandem reaction protocol
1. Introduction
exchange strategy as a facile, flexible and operationally simple
route to achieve this goal.
The development of new protocols for the protection of carbonyl
compounds in multistage synthetic sequences continues to attract
significant attention, and a diverse array of transformations have
been reported.1 The generation of acyclic and cyclic acetals in par-
ticular is one of the most widely used and popular protection
strategies, and recent interest in this area has lead to the de-
velopment of more efficient methodologies for both the formation
and deprotection of acetals and ketals.2 Additional interest in this
transformation has been generated by recent reports, which have
highlighted the significant benefits of employing acetals in place of
aldehydes and ketones in a diverse range of synthetic trans-
formations.3 Despite this considerable body of work, substrate
scope continues to be a limiting factor, in particular, for the pro-
tection of unreactive ketones especially in the presence of ther-
mally labile or acid sensitive functionality. Typical procedures for
the acetalisation of these substrates require the use of extended
reaction times, elevated temperatures with azeotropic removal of
water, and the requirement to use environmentally unacceptable
solvents. As part of an ongoing programme to develop highly effi-
cient and environmentally benign reaction processes,4 we required
access to both acylic and cyclic acetals derived from aromatic ke-
tones, and were attracted to the potential of developing an acetal
2. Results and discussion
Indium(III) salts have found widespread application in organic
synthesis as highly effective, hydrolytically stable and non-toxic
Lewis acid catalysts.5 During our own studies on the de-
velopment of new protocols employing these reagents, we dem-
onstrated that indium(III) triflate (In(OTf)3) is a highly efficient
catalyst for the rapid formation of both cyclic and acyclic acetals
and ketals6 under extremely mild reaction conditions. Disap-
pointingly, reactions employing deactivated aromatic ketones
provided only moderate conversions to ketal products, due to the
establishment of an equilibrium favouring the carbonyl compound.
It occurred to us that this problem might be addressed by consid-
ering a strategy in which an acyclic acetal was generated from
trimethyl orthoformate (TMOF) under In(OTf)3 catalysis in the
presence of a diol or triol. The acyclic acetal, once generated, un-
dergoes a subsequent In(OTf)3 catalysed transacetalisation reaction
to give the more stable cyclic acetal (Scheme 1).
Such exchange processes are well established in carbohydrate
chemistry,7 but have attracted significantly less attention in car-
bonyl protection strategies.8 With this goal in mind, we initially
considered the reactions of simple acylic acetals, such as benzal-
dehyde dimethylacetal 1, in the presence of catalytic quantities of
In(OTf)3 and ethane-1,2-diol to verify the potential of In(OTf)3 as
a transacetalisation catalyst. Gratifyingly, the exchange reaction
* Corresponding author. E-mail addresses: AEGraham@Glamorgan.ac.uk, aegra-
ham@glam.ac.uk (A.E. Graham).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.048

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B.M. Smith et al. / Tetrahedron 68 (2012) 7775e7781
In(OTf)3 (cat.)
ethane-1,2-diol
In(OTf)3 (cat.)
TMOF
MeO OMe
R1 R2
O
O
O
R1
R2
R1
R2
Scheme 1. Indium triflate mediated acetal exchange reaction.
proceeded rapidly to give near quantitative conversions to the
desired cyclic product using low catalyst loadings. The generality of
the reaction was demonstrated using a range of acylic acetals and
ketals in the presence of a small excess of the diol. Reactions of
dimethyl- or diethyl-acetals proceeded rapidly at room tempera-
ture in the presence of 1 mol % of the catalyst to provide the cor-
responding cyclic acetals in excellent isolated yields (Table 1,
entries 1e6). Most gratifying was the observation that dimethyl-
and diethyl-ketals also underwent rapid exchange reactions under
these conditions to provide cyclic ketals, again in excellent isolated
yields (entries 7 and 8). The products of these reactions require
minimal purification, achieved simply by passage of the crude re-
action mixture through a short plug of basic aluminium oxide to
remove the catalyst and small quantities of unreacted diol. This
protocol was also successfully extended to the reaction of triols, and
the reaction of 1 with glycerol provided near quantitative conver-
sion to the corresponding cis- and trans-cyclic dioxolane 2 and cis-
and trans-1,3-dioxane 3 products (entry 9).9
With conditions for efficient transacetalisation under indiu-
m(III) catalysis established, we next extended the protocol to em-
ploy solvent-free conditions. There has been considerable recent
interest in the development of such reaction processes, due not
only to their improved environmental profile, but also because of
the potential for improved chemoselectivity, reaction rates and
yields.10 With this goal in mind, we investigated reactions of 1 with
a series of diols and triols under solvent-free conditions, and were
delighted to observe complete conversion to the corresponding
cyclic acetals under conditions similar to those previously
employed (Table 2). The protocol is again applicable to both di-
methyl- and diethyl-ketals, which readily underwent rapid and
complete exchange to provide the corresponding cyclic ketals in
excellent isolated yields (entries 1e9). Reactions employing glyc-
erol were also effective giving excellent yields of cyclic acetal and
ketal products (entries 10e12), as did reactions employing
substituted 1,2-diols (entries 13e15).
With the scope of the In(OTf)3 catalysed transacetalisation re-
action established, we next addressed the key issue of whether this
methodology could be further developed to encompass the re-
actions of deactivated ketones in tandem acetalisation-acetal ex-
change reaction sequences. Such tandem reaction protocols have
attracted considerable recent interest due to the improvements in
efficiency, and the benefits of producing reactive or unstable species
in situ.11 Our initial studies considered the reaction of acetophenone
with 1 equiv of TMOF in the presence of ethane-1,2-diol, and grati-
fyingly, this reaction proceeded readily at room temperature to give
high conversions of the ketone to the cyclic ketal product. Conver-
sions could be further improved by increasing the quantity of TMOF
to 1.5 equiv, and under these conditions, near quantitative yields of
the cyclic ketal were achieved demonstrating the potential of this
approach (Table 3, entry 1). In the absence of TMOF, only trace
quantities of the acetal product were obtained. The reaction appears
to be general for the synthesis of a range of ketals from various diols
(entries 1e3) and triol (entry 4), and is tolerant of ring substituents
(entries 5 and 6), however, these latter reactions require longer re-
action times to achieve acceptable yields. Finally, we considered the
reactions of benzophenone, and were delighted to observe that this
sterically and electronically deactivated substrate readily provided
high yields of cyclic ketal products derived from diol (entry 7) or
glycerol (entry 8). Reaction of acetophenone and 2,2-dimethyl-1,3-
propanediol in the presence of triethyl orthoformate (TEOF) and
In(OTf)3 also proceeded rapidly to give excellent isolated yields of
the corresponding dioxane product. In contrast, the reaction of
benzophenone and propane-1,2-diol under these conditions pro-
vided only moderate conversions to the dioxane product.
Table 1
Acetal exchange reactions catalysed by In(OTf)3
1 mol% In(OTf)3
R3O OR3
n
n = 0 or 1
O
O
R1
R2
1.1 equiv diol, CH2Cl2, rt, 30 min
R1
R2
R3 = Me or Et
Entry
Acetal
Producta
Yielda (%)
90
OMe
O
O
1
2
O
O
Ph
Ph
OMe
Ph
Ph
OMe
OMe
92
95
OMe
OMe
O
3
4
Ph
Ph
Ph
Ph
O
OEt
OEt
OMe
OMe
O
93
85
O
O
5
O
O2N
O2N
Br
OMe
OMe
O
6
89
87
O
Br
OEt
OEt
O
7
8
O
MeO OMe
85
O
O
OH
OH
+
OMe
9
93b
O
Ph
O
H
O
O
H
Ph
OMe
Ph
2
3
a
All compounds gave satisfactory spectroscopic data.
Isolated as a 1.0:1.4:2.1:0.8 mixture of (trans) and (cis)-2 and (trans) and (cis)-3
b
as determined by 1H NMR spectroscopic analysis of the crude reaction mixture.

B.M. Smith et al. / Tetrahedron 68 (2012) 7775e7781
7777
Table 2
Acetal exchange reactions of diols and triols under solvent-free reaction conditions
1 mol% In(OTf)3
1.1 equiv diol, neat, rt, 30 min
R3O OR3
R1 R2
R3 = Me or Et
n
n = 0 or 1
O
O
R1
R2
Entry
1
Acetal
Producta
Yielda (%)
OMe
OMe
O
O
92
89
96
Ph
Ph
Ph
Ph
OMe
OMe
O
2
3
Ph
O
OMe
OMe
O
Ph
O
OMe
OMe
O
4
85
O
MeO
MeO
O
OMe
5
6
88
90
O
OMe
O
OEt
OEt
O
OMe
OMe
O
7
92
O
MeO OMe
8
91
95
O
O
MeO OMe
OMe
9
O
O
OH
OH
10
95b
O
Ph
O
H
+
O
O
H
Ph
OMe
Ph
2
3
O
OMe
OMe
11
12
84
O
OH
OH
MeO OMe
88
O
O
(continued on next page)

7778
B.M. Smith et al. / Tetrahedron 68 (2012) 7775e7781
Table 2 (continued )
Entry
Acetal
Producta
Yielda (%)
83
Ph
MeO OMe
O
13
14
O
Ph
MeO OMe
MeO OMe
O
79
76
O
15
O
O
a
All compounds gave satisfactory spectroscopic data.
b
Isolated as a 1.0:1.3:2.6:1.1 mixture of (trans) and (cis)-2 and (trans) and (cis)-3 as determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
Finally, we turned our attention to gaining an insight into the
precise course of this reaction. Our original premise envisaged an
initial acetalisation reaction, which proceeds through an in-
termediate O-methyl oxonium intermediate to give the acyclic ac-
etal product. In the presence of a diol, this O-methyl oxonium
intermediate is intercepted to generate the corresponding cyclic
product (Scheme 2; pathway 1). A number of other mechanistic
interpretations are possible, in particular, that the ketal product is
produced by the In(OTf)3 catalysed reaction of the ketone with an
acetalisation reagent formed by an initial In(OTf)3 promoted ex-
change reaction between TMOF and diol (Scheme 2; pathway 2).
Indeed, both 2-methoxy-1,3-dioxolane and 2-methoxy-1,3-dioxane
have been reported to function as efficient acetalisation reagents in the
presence of acid catalysts, however, these procedures employextended
reaction times under forcing reaction conditions, suggesting that this
explanation is unlikely.12 In order to establish further whether this
pathway was responsible for the improved yields observed, we carried
out a short series of reactions inwhich 1 mol % of In(OTf)3 was added to
a mixture of either ethane-1,2-diol or propane-1,3-diol and TMOF un-
der our standard reaction conditions. This was allowed to react at room
temperature for 1 h before the addition of 1 equiv of acetophenone. We
envisaged that if a 2-methoxy substituted dioxane or dioxolane was
acting as the acetalisation reagent, then the yields from these reactions
should be broadly similar to those observed for reactions inwhich all of
the components were present at the start. 1H NMR spectroscopic
analysis of these crude reaction mixtures, however, revealed poor
conversions to the ketal product, with only 5% of the dioxolane product
produced from the reaction containing ethane-1,2-diol, and 30% of the
dioxane product generated from the reaction containing propane-1,3-
diol. Additional experiments involving 1H NMR spectroscopic analysis
of reaction mixtures prior to acetophenone addition indicated that
while the TMOF is rapidly consumed, the expected 2-methoxy-1,3-
dioxolane or 2-methoxy-1,3-dioxane products were only present in
small amounts, with the major product apparently being a trimeric
material 4, presumably formed by an In(OTf)3 catalysed alcohol ex-
change process (Scheme 3). There is good literature precedent for such
alcohol exchange processes, which readily occur under acid catalysis.13
Furthermore, GCeMS analysis of crude reaction mixtures from
transformations containing benzophenone, TMOF and propane-
1,3-diol, generated under our standard tandem acetalisation-acetal
exchange conditions, revealed the presence of small quantities of
benzophenone dimethylacetal. While the possibility that TMOF is
acting as a dehydrating agent in these reactions cannot at this point
be discounted, the presence of the acyclic dimethylacetal in these
reaction mixtures is evidence that the ketal products are formed by
a transacetalisation process.
3. Conclusions
In conclusion, we have demonstrated that In(OTf)3 efficiently
catalyses the transacetalisation reactions of acyclic acetals to cyclic
acetals with diols and triols under extremely mild reaction con-
ditions. These transformations use low catalyst loadings to provide
excellent isolated yields of both cyclic acetal and ketal products.
The process is highly efficient, employing near-stoichiometric
quantities of the diol, and proceeds rapidly at room tempera-
ture. Furthermore, the reaction can be adapted to employ solvent-
free conditions, further improving overall efficiency. We have
further extended our studies in this area to develop a tandem
acetalisation-acetal exchange protocol, again under solvent-free
conditions, which is applicable to the synthesis of cyclic ketals
from unreactive aromatic ketones, such as acetophenone and
benzophenone. These ketals are produced in high yields under
very mild reaction conditions without the requirement to use high
temperatures, azeotropic removal of water or extended reaction
times.
4. Experimental
4.1. General methods
Commercially available reagents were used without further
purification. Ethane-1,2-diol and propane-1,3-diol were stored
over activated 4 A molecular sieves prior to use. Product purifi-
ꢀ
cation was achieved using basic aluminium oxide (Brockmann
grade 1). Analytical thin layer chromatography was carried out
using aluminium-backed plates coated with Merck Kieselgel 60
GF254 that were visualized under UV light (at 254 and/or 360 nm)
or using potassium permanganate solution (1% in water) followed
by charring. Infrared (IR) spectra were recorded in the range
4000e600 cmꢀ1 as neat oils or solids and are reported in cmꢀ1
.
Nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker 400 MHz or a Jeol 270 MHz spectrometer in CDCl3 at
25 ꢁC and are reported in parts per million; J values are recorded
in hertz and multiplicities are expressed by the usual conventions.
Low-resolution mass spectra (MS) were determined using the
ionisation technique stated. ES refers to electrospray ionisation
and EI refers to electron impact ionisation. High-resolution mass
spectra (HRMS) were obtained courtesy of the EPSRC Mass
Spectrometry Service, Swansea University, UK using the ionisation
method specified. Removal of solvent refers to evaporation at
reduced pressure using a rotary evaporator followed by the re-
moval of trace volatiles using a vacuum pump.

B.M. Smith et al. / Tetrahedron 68 (2012) 7775e7781
7779
Table 3
Tandem acetalisation-acetal exchange reactions of deactivated ketones under solvent-free reaction conditions
R R
O
n
R2
1 mol% In(OTf)3, TMOF (1.5 equiv.)
O
O
R2
1.1 equiv diol, rt, neat
R1
R1
Entry
1
Ketone
Product
Time (h)
Yielda (%)
O
O
1
87b
88c
91
O
Ph
CH3
Ph
CH3
O
O
O
2
3
4
1
1
2
O
O
Ph
Ph
Ph
CH3
CH3
CH3
Ph
CH3
O
O
Ph
CH3
OH
78d
O
CH3
O
Ph
O
O
O
CH3
CH3
CH3
5
6
7
2
2
2
2
81
79
NO2
NO2
O
O
O
CH3
NO2
Ph
NO2
O
85e
O
Ph
O
Ph
Ph
OH
O
8
72
O
O
Ph
Ph
Ph
Ph
a
All compounds gave satisfactory spectroscopic data.
b
c
Approximately 1% conversion to acetal in the absence of TMOF as determined by GCeMS analysis of the crude reaction mixture.
Reaction employing TEOF (1.5 equiv) provided 91% isolated yield of dioxane product.
d
e
Conversion to dioxolane determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
Reaction employing TEOF (1.5 equiv) provided 70% conversion to dioxane product.
4.2. Typical experimental procedure for the In(OTf)3 catalysed
acetal exchange reaction
was removed and the reaction mixture was passed through a short
plug of basic alumina, which was then washed with hexane
(2ꢂ2 mL) and the solvent removed under reduced pressure to give
the product, as a colourless oil (183 mg, 95%); 1H NMR (CDCl3;
4.2.1. 5,5-Dimethyl-2-phenyl-[1,3]-dioxane.3g In(OTf)3
10 mol, 1 mol %) was added to a mixture of benzaldehyde dime-
(5.6 mg,
m
400 MHz)
(2H, d, J¼11.0 Hz), 5.45 (1H, s), 7.25e7.35 (3H, m), 7.45e7.55 (2H,
m); 13C NMR (CDCl3; 100 MHz)
¼138.4, 128.8, 128.2, 126.1, 101.7,
77.6, 30.2, 22.9, 21.8; nmax (film)/cmꢀ1 (neat) 2954, 2846, 1388, 1101,
d
¼0.75 (3H, s), 1.25 (3H, s), 3.60 (2H, d, J¼11.0 Hz), 3.80
thylacetal (152 mg, 1.00 mmol) and 2,2-dimethyl-1,3-propanediol
(111 mg, 1.10 mmol) in CH2Cl2 (2 mL) and the reaction mixture
stirred at room temperature for 30 min. At this time, the solvent
d

7780
B.M. Smith et al. / Tetrahedron 68 (2012) 7775e7781
Me
R1
In(OTf)
3
MeO
R1
OMe
R2
O
(MeO)3CH
O
R2
R1
R2
O
In(OTf)
In(OTf)
3
3
pathway 2
pathway 1
HO
OH
HO
OH
R1
R2
O
H
O
OMe
O
O
In(OTf)
R1
R2
3
Scheme 2.
Scheme 3.
1017, 745, 696; MS (EI) m/z 192; HRMS (ES) calculated for C12H17O2
(MþH)þ 193.1223, found (MþH)þ 193.1224.
2892, 1375, 1201, 1069, 733, 650; MS (EI) m/z 164; HRMS (ES) cal-
culated for C10H13O2 (MþH)þ 165.0916, found (MþH)þ 165.0917.
Acknowledgements
4.3. Typical experimental procedure for the In(OTf)3 catalysed
acetal exchange reaction under solvent-free conditions
The authors thank the Engineering and Physical Sciences Re-
search Council and the Royal Society of Chemistry for financial
support, and the EPSRC National Mass Spectrometry Service,
Swansea University.
4.3.1. 3,3-Dimethyl-1,5-dioxa-spiro[5.5]undecane.3f In(OTf)3
(5.6 mg, 10 mmol, 1 mol %) was added to a mixture of cyclohexanone
dimethylacetal (144 mg,1.00 mmol) and finely ground 2,2-dimethyl-
1,3-propanediol (111 mg,1.10 mmol) and the reaction mixture stirred
at room temperature for 30 min. At this time, residual MeOH was
removed under reduced pressure and the crude residue passed
throughashortplugofbasicalumina,whichwaswashedwithhexane
(2ꢂ2 mL). The solvent was removed under reduced pressure to give
the product, as a colourless oil (170 mg, 92%); 1H NMR (CDCl3;
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.048.
400 MHz)
d
¼0.90 (6H, s), 1.30e1.75 (10H, m), 3.45 (4H, s); 13C NMR
References and notes
(CDCl3; 100 MHz)
d
¼97.7, 69.8, 32.6, 30.2, 25.8, 22.8, 22.6; nmax (film)/
1. (a) Wuts, P. G. M.; Green, T. W. Protective Groups in Organic Synthesis; John Wiley
& Sons: New York, NY, 2006; (b) Kocienski, P. J. Protecting Groups; Thieme: New
York, NY, 2003; (c) Yu, M.; Pagenkopf, B. L. Tetrahedron 2003, 59, 2765e2771.
2. (a) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004,
104, 199e250; (b) Williams, D. B. G.; Lawton, M. C. Green Chem. 2008, 10,
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cmꢀ1 (neat) 2936, 2858, 1104, 914, 733; MS (EI) m/z 184; HRMS (ES)
calculated for C11H21O2 (MþH)þ 185.1536, found (MþH)þ 185.1537.
4.4. Typical experimental procedure for tandem acetalisation-
acetal exchange under solvent-free conditions
4.4.1. 2-Methyl-2-phenyl-1,3-dioxolane.2g In(OTf)3 (5.6 mg, 10
1 mol %) was added to mixture of acetophenone (120 mg,
mmol,
a
1.00 mmol), trimethyl orthoformate (159 mg, 1.50 mmol) and
ethane-1,2-diol (68 mg, 1.10 mmol) and the reaction mixture stirred
at room temperature for 1 h. At this time, residual MeOH was re-
moved under reduced pressure and the crude product passed
through a short plug of basic alumina, which was washed with
hexane (2ꢂ2 mL). The solvent was removed under reduced pressure
to give the product as a light yellow oil (143 mg, 87%); 1H NMR
(CDCl3; 400 MHz)
d
¼1.65 (3H, s), 3.70e3.85 (2H, m), 3.95e4.05 (2H,
m), 7.25e7.40 (3H, m), 7.45e7.55 (2H, m); 13C NMR (CDCl3; 100 MHz)
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Taylor, S. H.; Graham, A. E. J. Mol. Catal., A: Chem. 2010, 329, 57e63; (b)
d
¼143.5, 128.3, 127.9, 125.3, 108.8, 64.2, 27.5; nmax (film)/cmꢀ1 (neat)

B.M. Smith et al. / Tetrahedron 68 (2012) 7775e7781
7781
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